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High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin

Abstract

In thalassemia, deficient globin-chain production during erythropoiesis results in anemia1,2,3. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death4. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism5. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 ± 50 pg/ml. In comparison, individuals with β-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 ± 9,600 pg/ml; range 4,800–248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.

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Figure 1: Transcriptional profiling of TGFB superfamily members during erythropoiesis.
Figure 2: GDF15 concentration in human blood and correlation with concentrations of hemoglobin, erythropoietin, soluble transferrin receptor and ferritin in blood from thalassemia patients.
Figure 3: Regulation of hepcidin mRNA expression by GDF15.
Figure 4

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References

  1. Rund, D. & Rachmilewitz, E. β-thalassemia. N. Engl. J. Med. 353, 1135–1146 (2005).

    CAS  Article  Google Scholar 

  2. Pootrakul, P. et al. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in Thai patients with thalassemia. Blood 96, 2606–2612 (2000).

    CAS  PubMed  Google Scholar 

  3. Nathan, D.G. Thalassemia as a proliferative disorder. Medicine (Baltimore) 43, 779–782 (1964).

    CAS  Article  Google Scholar 

  4. Weatherall, D.J. & Clegg, J.B. The Thalassaemia Syndromes (4th ed.) (Blackwell Scientific, Oxford, 2001).

    Book  Google Scholar 

  5. Nemeth, E. & Ganz, T. Regulation of iron metabolism by hepcidin. Annu. Rev. Nutr. 26, 323–342 (2006).

    CAS  Article  Google Scholar 

  6. Donovan, A., Roy, C.N. & Andrews, N.C. The ins and outs of iron homeostasis. Physiology (Bethesda) 21, 115–123 (2006).

    CAS  Google Scholar 

  7. Ganz, T. Hepcidin—a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract. Res. Clin. Haematol. 18, 171–182 (2005).

    CAS  Article  Google Scholar 

  8. Papanikolaou, G. et al. Hepcidin in iron overload disorders. Blood 105, 4103–4105 (2005).

    CAS  Article  Google Scholar 

  9. Kattamis, A. et al. The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major. Haematologica 91, 809–812 (2006).

    CAS  PubMed  Google Scholar 

  10. Weizer-Stern, O. et al. Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell–line HepG2 induced by thalassaemic sera. Br. J. Haematol. 135, 129–138 (2006).

    CAS  Article  Google Scholar 

  11. Wang, R.H. et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2, 399–409 (2005).

    CAS  Article  Google Scholar 

  12. Babitt, J.L. et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat. Genet. 38, 531–539 (2006).

    CAS  Article  Google Scholar 

  13. Truksa, J., Peng, H., Lee, P. & Beutler, E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc. Natl. Acad. Sci. USA 103, 10289–10293 (2006).

    CAS  Article  Google Scholar 

  14. Massague, J. TGF-β signal transduction. Annu. Rev. Biochem. 67, 753–791 (1998).

    CAS  Article  Google Scholar 

  15. de Caestecker, M. The transforming growth factor-β superfamily of receptors. Cytokine Growth Factor Rev. 15, 1–11 (2004).

    CAS  Article  Google Scholar 

  16. Wojda, U., Noel, P. & Miller, J.L. Fetal and adult hemoglobin production during adult erythropoiesis: coordinate expression correlates with cell proliferation. Blood 99, 3005–3013 (2002).

    CAS  PubMed  Google Scholar 

  17. Yamamoto, Y. & Oelgeschlager, M. Regulation of bone morphogenetic proteins in early embryonic development. Naturwissenschaften 91, 519–534 (2004).

    CAS  Article  Google Scholar 

  18. Sritippayawan, S. et al. Restrictive lung disease and serum TGF-β1 in thalassemia major children. Asian Pac. J. Allergy Immunol. 23, 121–126 (2005).

    CAS  PubMed  Google Scholar 

  19. Eling, T.E. et al. NSAID activated gene (NAG-1), a modulator of tumorigenesis. J. Biochem. Mol. Biol. 39, 649–655 (2006).

    CAS  PubMed  Google Scholar 

  20. Marjono, A.B. et al. Macrophage inhibitory cytokine-1 in gestational tissues and maternal serum in normal and pre-eclamptic pregnancy. Placenta 24, 100–106 (2003).

    CAS  Article  Google Scholar 

  21. Hromas, R. et al. PLAB, a novel placental bone morphogenetic protein. Biochim. Biophys. Acta 1354, 40–44 (1997).

    CAS  Article  Google Scholar 

  22. Millard, K.N., Frazer, D.M., Wilkins, S.J. & Anderson, G.J. Changes in the expression of intestinal iron transport and hepatic regulatory molecules explain the enhanced iron absorption associated with pregnancy in the rat. Gut 53, 655–660 (2004).

    CAS  Article  Google Scholar 

  23. Welsh, J.B. et al. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc. Natl. Acad. Sci. USA 100, 3410–3415 (2003).

    CAS  Article  Google Scholar 

  24. Koopmann, J. et al. Serum markers in patients with resectable pancreatic adenocarcinoma: macrophage inhibitory cytokine 1 versus CA19–9. Clin. Cancer Res. 12, 442–446 (2006).

    CAS  Article  Google Scholar 

  25. Yang, H., Filipovic, Z., Brown, D., Breit, S.N. & Vassilev, L.T. Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation. Mol. Cancer Ther. 2, 1023–1029 (2003).

    CAS  PubMed  Google Scholar 

  26. Xu, J. et al. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ. Res. 98, 342–350 (2006).

    CAS  Article  Google Scholar 

  27. Hsiao, E.C. et al. Characterization of growth-differentiation factor 15, a transforming growth factor β superfamily member induced following liver injury. Mol. Cell. Biol. 20, 3742–3751 (2000).

    CAS  Article  Google Scholar 

  28. Kearney, S.L. et al. Urinary hepcidin in congenital chronic anemias. Pediatr. Blood Cancer 48, 57–63 (2007).

    Article  Google Scholar 

  29. Rao, K.R., Patel, A.R., McGinnis, P. & Patel, M.K. Iron stores in adults with sickle cell anemia. J. Lab. Clin. Med. 103, 792–797 (1984).

    CAS  PubMed  Google Scholar 

  30. Inamura, J. et al. Upregulation of hepcidin by interleukin-1β in human hepatoma cell lines. Hepatol. Res. 33, 198–205 (2005).

    CAS  Article  Google Scholar 

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Acknowledgements

The National Institutes of Health Department of Transfusion Medicine, National Institute of Diabetes and Digestive and Kidney Diseases Microarray Core Laboratory, and S. Strom, J. Goodnough, G. Moser and M. Ehinger performed or assisted with studies involving hepatocytes and transgenic mice. We thank C. Deng, C. Philpott, and A. Schechter for critical reading of the manuscript. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

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T. T., manuscript writing, performed experiments, assembly of data. N.V.B., collection and assembly of array data. P.A.O., collection of clinical samples and data. S.-H.G., provision of study material, array data analysis. P.S., collection of clinical samples and data. Y.T.L., collection and assembly of array data. J.W.M., collection of clinical samples. C.H.R., collection of clinical samples and data. N.L.C.L., collection of clinical samples and data. R.-H.W., expertise with hepatic iron assessment. T.E., expertise with GDF15 transgenic mouse. R.C., collection of clinical samples and data. T.G., mouse GDF15 analyses, manuscript revision. S.F.L., collection of clinical samples and data. S.F., collection of clinical samples and data. J.L.M., manuscript writing, experimental conception and design, assisted and supervised research team.

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Correspondence to Jeffery L Miller.

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A provisional patent (Application No. 601864.705) was generated on the basis of these findings.

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Tanno, T., Bhanu, N., Oneal, P. et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13, 1096–1101 (2007). https://doi.org/10.1038/nm1629

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